NIH study found 58% of patients with treatment-naïve severe aplastic anemia (SAA) achieved a complete response when eltrombopag was given at the initiation of and concurrently with standard immunosuppressive therapy

The historical complete response rate was 10% for untreated patients with SAA on immunosuppressive therapy alone

Findings were published in The New England Journal of Medicine (NEJM) and will be submitted to regulatory bodies for treatment-naïve SAA

- Novartis today announced the publication of a study conducted by the National Heart, Lung, and Blood Institute (NHLBI) of the National Institutes of Health (NIH) demonstrating that 58% of patients with treatment-naïve severe aplastic anemia (SAA) achieved complete response at six months when treated with eltrombopag at the initiation of and concurrently with standard immunosuppressive treatment. The study evaluated three sequential treatment groups, or cohorts. Cohort 3 added eltrombopag at the initiation of immunosuppressive therapy and showed a higher complete response rate than cohorts 1 and 2, where eltrombopag was initiated on day 14. The data is published in the latest issue of The New England Journal of Medicine.

SAA is a rare and serious blood disorder in which a patient’s bone marrow fails to make enough red blood cells, white blood cells and platelets. As a result, people living with SAA may experience debilitating symptoms and complications, such as fatigue, trouble breathing, recurring infections and abnormal bruising or bleeding that can limit their daily activities. The current standard of care includes immunosuppressive therapy (IST) or hematopoietic stem cell transplantation. However, one-quarter to one-third of patients will not respond to IST and 30-40% of responders will relapse, causing symptoms to return.

"Our research in NEJM shows that eltrombopag plus standard immunosuppressive therapy appeared to increase the overall response rate and substantially increase the frequency, speed and robustness of hematologic recovery in patients with SAA compared to historical controls," said the study’s lead author, Danielle Townsley, MD, researcher in the NHLBI.

In the NIH study, the primary efficacy endpoint of complete response rate with eltrombopag plus standard immunosuppressive treatment at six months exceeded the historic rate (10%) across all three treatment cohorts (cohorts differed in length of eltrombopag administration; dose adjusted by age) . Patients in cohort 1 received eltrombopag from day 14 to six months and achieved a complete response rate of 33%. The complete response was lowest in cohort 2 (26%), in which eltrombopag exposure was shortest (day 14 to three months). Furthermore, overall increases in platelet and neutrophil blood level counts were higher in comparison to the historic cohort, which is a key treatment goal for SAA , . The overall survival rate at a median follow-up of two years was 97% (95% CI, 94-100%) for all cohorts.

"We are committed to improving the care of people living with serious conditions over the long term, particularly those with few options and great unmet need," said Vasant Narasimhan, Global Head, Drug Development and Chief Medical Officer, Novartis. "Eltrombopag is the only thrombopoietin receptor agonist to be used in the second-line treatment of SAA, and these results from the NIH study now show its potential as a first-line treatment, which we look forward to discussing with health authorities."

The study also looked at clonal evolution, which is a major complication of SAA (with potential for development of myelodysplastic syndrome and acute myeloid leukemia) . As of May 25, 2016, the addition of eltrombopag did not increase the rate of clonal evolution and was not higher compared to historical data , , , . Clonal cytogenetic evolution occurred in 7 patients at 2 years (95% CI, 1-14%) .

The safety profile was consistent with the known safety profile of eltrombopag. Eltrombopag was briefly discontinued during the first two weeks in 7 patients who experienced transient liver enzyme elevations. Two severe adverse events, grade 2-3 cutaneous eruptions, were attributed to eltrombopag and required discontinuation of the drug. Adverse events not attributed to eltrombopag were due to neutropenic infections and known toxicities from immunosuppressive therapy. One death occurred on study in a non-responding patient with thymoma three months following treatment, due to paraneoplastic encephalopathy.

NIH Study DesignThe Phase I-II, non-randomized study is being conducted by the National Heart, Lung and Blood Institute through a Cooperative Research and Development Agreement (CRADA) with Novartis Pharmaceuticals Corporation. The primary analysis included 92 patients with treatment-naïve severe aplastic anemia in three treatment cohorts, and nearly 80% of patients were over the age of 18. Eltrombopag was administered at 150 mg daily for patients 12 years or older, 75 mg daily for those 6 to 11 years, and 2.5 mg/kg/day for children 2 to 5 years. Duration of treatment with eltrombopag varied per cohort (cohort 1: day 14 to six months; cohort 2: day 14 to three months; cohort 3: day one to six months). ATG and cyclosporine were administered as standard immunosuppression therapy.

About EltrombopagEltrombopag, marketed as Promacta in the US and Revolade in countries outside the US, is approved in more than 100 countries worldwide for the treatment of thrombocytopenia in adult patients with chronic immune (idiopathic) thrombocytopenic purpura (ITP) who have had an inadequate response or are intolerant to other treatments, in over 45 countries worldwide for the treatment of patients with severe aplastic anemia (SAA) who are refractory to other treatments, and in more than 50 countries for the treatment of thrombocytopenia in patients with chronic hepatitis C to allow them to initiate and maintain interferon-based therapy. Eltrombopag is approved in the United States and in the European Union for the treatment of thrombocytopenia in pediatric patients 1 year and older with chronic immune (idiopathic) thrombocytopenia (ITP) who have had an insufficient response to corticosteroids, immunoglobulins, or splenectomy.

Important Safety Information for Revolade (eltrombopag) Revolade may cause serious side effects, such as liver problems, high platelet counts and a higher chance for blood clots, bleeding after stopping treatment, and bone marrow problems.

Revolade may damage the liver and cause serious, even life threatening, illness. Blood tests to check the liver are needed before taking Revolade and during treatment. When certain antiviral treatments are given together with Revolade for the treatment of thrombocytopenia due to hepatitis C virus (HCV) infections, some liver problems can get worse.

A doctor will order the blood tests and any other tests required. In some cases, Revolade treatment may need to be stopped. Patients should tell a doctor right away if they have any of these signs and symptoms of liver problems: yellowing of the skin or the whites of the eyes (jaundice), unusual darkening of the urine, unusual tiredness, right upper stomach area pain.

Patients have a higher chance of getting a blood clot if their platelet count is too high during treatment with Revolade, but blood clots can occur with normal or even low platelet counts. Patients who have cirrhosis of the liver are at risk of a blood clot in a blood vessel that feeds the liver. Patients may have severe complications from some forms of blood clots, such as clots that travel to the lungs or that cause heart attacks or strokes. A doctor will check the patient’s blood platelet counts, and change the dose or stop Revolade if platelet counts get too high. Patients should tell their doctor right away if they have signs and symptoms of a blood clot in the leg, such as swelling or pain/tenderness of one leg.

When patients with chronic ITP stop taking Revolade, their blood platelet count will drop back down to what it was before they started taking Revolade. These effects are most likely to happen within 4 weeks after patients stop taking Revolade. The lower platelet counts may increase risk of bleeding. A doctor will check platelet counts for at least 4 weeks after patients stop taking Revolade. Patients should tell their doctor or pharmacist if they have any bruising or bleeding after they stop taking Revolade.

Patients being treated for the disease may have problems with their bone marrow. Medicines like Revolade could make this problem worse. Signs of bone marrow changes may show up as abnormal results in blood tests. A doctor may also carry out tests to directly check the bone marrow during treatment with Revolade.

The most common side effects of Revolade when used to treat pediatric patients with chronic ITP include upper respiratory tract infection, nasopharyngitis, cough, diarrhea, pyrexia, rhinitis, abdominal pain, oropharyngeal pain, toothache, rash, increased AST and rhinorrhea.

The most common side effects of Revolade when used to treat patients with chronic HCV and antiviral agents include headache, anemia, decreased appetite, insomnia, cough, nausea, diarrhea, alopecia, pruritus, myalgia, pyrexia, fatigue, influenza-like illness, asthenia, chills and peripheral edema.

The most common side effects of Revolade when used to treat patients with severe aplastic anemia (SAA) include headache, dizziness, insomnia, cough, dyspnea, oropharyngeal pain, rhinorrhea, nausea, diarrhea, abdominal pain, transaminases increased, ecchymosis, arthralgia, muscle spasms, pain in extremity, fatigue, febrile neutropenia, and pyrexia. Common side effects that may show up in blood tests include increase in some liver enzymes and laboratory tests that may show abnormal changes to the cells in the bone marrow.

Please see full EU Summary of Product Characteristics for Revolade (eltrombopag).